Charcot-Marie-Tooth (CMT) - Axonal Neuropathy Panel

Charcot Marie Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN) is a large group of inherited disorders of the peripheral nerves. The progressive degeneration of motor nerves results in weakness and atrophy of the distal muscles. The degeneration of sensory nerves leads to decreased sensation, tingling and numbness in the legs, feet, arms and hands and neuropathic pain. The age of onset varies from childhood to mid adulthood. Symptoms usually begin with weakness and atrophy in the muscles of the legs and feet. As the disease progresses, weakness and atrophy of the muscles of the arms and hands may occur. CMT is heterogeneous in regards to symptoms, severity and progression rate. Although the disease may lead to disability and respiratory difficulty, life expectancy is usually unaffected. Most common symptoms include foot deformity, loss of balance, hammertoes, foot drop, frequent tripping and falls, and reduced manual dexterity (Bird 2015). Diagnosis is based on clinical features, family history, neurological examination, and electromyography (EMG) and nerve conduction velocity (NCV) findings (Rossor 2013; Bird 2015). CMT affects approximately 1 in 3,300 people (Bird 2015; Saporta 2011). Axonal forms of CMT primarily affect the axons of the peripheral nerves and are characterized by normal or near normal NCV and reduced amplitudes. Demyelinating forms of CMT primarily affect the myelin sheath of the peripheral nerve and are characterized by slow nerve conduction velocities (NCV) of less than 38 m/s in upper limbs. Intermediate NCV of 25-45 m/s can be difficult to classify as axonal or demyelinating. This panel includes genes that cause a strict CMT2 (axonal) phenotype, in addition to genes that cause intermediate forms with axonal and/or demyelinating conductions.

Charcot-Marie-Tooth can be inherited in an autosomal dominant, autosomal recessive or an X-linked manner. The MPZ, NEFL, MFN2, RAB7, TRPV4, GARS1/GARS, HSPB1, HSPB8, INF2, GNB4, AARS1/AARS, DYNC1H1, LRSAM1, DHTKD1, MARS1/MARS, and KIF5A genes are involved in autosomal dominant CMT. Autosomal recessive forms of CMT involve the LMNA, MED25, HINT1, TRIM2, MTMR2, SBF2, SBF1, SH3TC2, PRX, FGD4, FIG4, NDRG1, KARS1/KARS, PLEKHG5, IGHMBP2 and COX6A1 genes. Pathogenic variants in the EGR2, GDAP1, and DNM2 genes can exhibit both dominant and recessive inheritance. In cases of Dejerine-Sottas syndrome, the MPZ and PRX genes can exhibit both dominant and recessive inheritance as well. Pathogenic variants in the AIFM1, PRPS1, and PDK3 genes are inherited in an X-linked manner. See individual gene test descriptions for information on molecular biology of gene products.

A genetic etiology can be identified in approximately 50-70% of individuals with CMT (Saporta et al. 2011; Rossor et al. 2013). Specifically, a molecular diagnosis can be identified in approximately 80-85% of individuals with demyelinating neuropathy (CMT1), and a molecular diagnosis can be identified in approximately 25-35% of individuals with axonal neuropathy (CMT2) (Bird 2015; Bird 2015; Rossor et al. 2013). The most common causative gene for CMT2 is MFN2 and accounts for about 10-20% of CMT2 cases (Bird 2015; Rossor 2013). The sensitivity of this panel will vary based on the clinical phenotype of the patient.

The IGHMBP2, MPZ, MTMR2, SBF2, PRX, FIG4, and NDRG1 are genes in this panel with large copy number variants reported; however, clinical sensitivity has not been determined with a large cohort study (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Please note that for technical reasons, exon 8 of the INF2 gene is not currently included this panel. Thus far, only exons 2 to 6, especially exons 2 to 4 that encode the diaphanous inhibitory domain (DID), have been reported to harbor pathogenic INF2 variants (Boyer et al. 2011; Barua et al. 2013; Human Gene Mutation Database).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).